Altropane, a SPECT or PET imaging probe for dopamine neurons: I. Dopamine transporter binding in primate brain

Increasing evidence suggests that the dopamine transporter is an important marker for physiological and pathological changes in dopamine neurons. Potent dopamine transport inhibitors of the phenyltropane series (e.g., WIN 35,428 or CFT) are particularly suitable for PET (positron emission tomography) or SPECT (single photon emission computed tomography) imaging of the dopamine transporter in living brain. We investigated whether altropane, an N-iodoallyl analog of WIN 35,428 (IACFT:E-N-iodoallyl-2 -carbomethoxy-3beta-(4-fluorophenyl)tropane), displayed in vitro properties suitable for evaluation as a SPECT imaging agent. In brain striatum of cynomolgus monkey (Macaca fascicularis), the unlabeled E-isomer (IC50: 6.62 +/- 0.78 nM) was more potent than the Z-isomer (IC50: 52.6 +/- 0.3 nM) and displayed a relatively high dopamine:serotonin transporter selectivity (28-fold). In radiolabeled form, [125I]altropane bound to sites in the striatum with a single high affinity (KD: 5.33 +/- 0.55 nM) and with a site density (BMAX: 301 pmol/g original wet tissue weight) that was within the density range reported previously for the dopamine transporter in striatum. Drugs inhibited [125I]altropane binding with a rank order of potency that corresponded closely to their potencies for inhibiting [3H]WIN 35,428 binding (r2: 0.99; P < 0.0001) to the blocking dopamine transport. The favorable binding properties of altropane, together with its rapid entry into primate brain and highly localized distribution in dopamine-rich brain regions, suggest it is a suitable iodinated probe for monitoring the dopamine transporter in vitro and in vivo by SPECT or PET imaging.